CN103044422A - Preparation method of praziquantel - Google Patents
Preparation method of praziquantel Download PDFInfo
- Publication number
- CN103044422A CN103044422A CN2012105959434A CN201210595943A CN103044422A CN 103044422 A CN103044422 A CN 103044422A CN 2012105959434 A CN2012105959434 A CN 2012105959434A CN 201210595943 A CN201210595943 A CN 201210595943A CN 103044422 A CN103044422 A CN 103044422A
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- reaction
- praziquantel
- solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- FSVJFNAIGNNGKK-UHFFFAOYSA-N 2-[cyclohexyl(oxo)methyl]-3,6,7,11b-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4-one Chemical compound C1C(C2=CC=CC=C2CC2)N2C(=O)CN1C(=O)C1CCCCC1 FSVJFNAIGNNGKK-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 229960002957 praziquantel Drugs 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims abstract description 11
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 claims abstract description 10
- 229940125758 compound 15 Drugs 0.000 claims abstract description 10
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims abstract description 7
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims abstract description 6
- 230000002829 reductive effect Effects 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 59
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 15
- 239000007810 chemical reaction solvent Substances 0.000 claims description 10
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims description 9
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims description 9
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 229940126543 compound 14 Drugs 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 8
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims description 7
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 7
- 229940125797 compound 12 Drugs 0.000 claims description 7
- 229940126142 compound 16 Drugs 0.000 claims description 7
- 239000011591 potassium Substances 0.000 claims description 7
- 229910052700 potassium Inorganic materials 0.000 claims description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 238000007363 ring formation reaction Methods 0.000 claims description 6
- RVOJTCZRIKWHDX-UHFFFAOYSA-N cyclohexanecarbonyl chloride Chemical compound ClC(=O)C1CCCCC1 RVOJTCZRIKWHDX-UHFFFAOYSA-N 0.000 claims description 5
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 5
- 239000004471 Glycine Substances 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 235000015320 potassium carbonate Nutrition 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 3
- 229960003280 cupric chloride Drugs 0.000 claims description 3
- 239000000376 reactant Substances 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 17
- 239000003814 drug Substances 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000013461 design Methods 0.000 abstract description 2
- 239000000273 veterinary drug Substances 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 239000010410 layer Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 238000000967 suction filtration Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- 238000010792 warming Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 230000006837 decompression Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- LAOOXBLMIJHMFO-UHFFFAOYSA-N 1-[2-(diethylamino)ethylamino]-4-methylthioxanthen-9-one;hydron;chloride Chemical compound Cl.S1C2=CC=CC=C2C(=O)C2=C1C(C)=CC=C2NCCN(CC)CC LAOOXBLMIJHMFO-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- WDLUEZJSSHTKAP-UHFFFAOYSA-N acetaldehyde;1,1-diethoxyethane Chemical compound CC=O.CCOC(C)OCC WDLUEZJSSHTKAP-UHFFFAOYSA-N 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- -1 glycyl halogen Chemical class 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 125000001475 halogen functional group Chemical group 0.000 description 2
- 230000002147 killing effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 230000000630 rising effect Effects 0.000 description 2
- 230000001843 schistosomicidal effect Effects 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 241000242722 Cestoda Species 0.000 description 1
- 241001327965 Clonorchis sinensis Species 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 206010014096 Echinococciasis Diseases 0.000 description 1
- 208000009366 Echinococcosis Diseases 0.000 description 1
- 241000244160 Echinococcus Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- ASJGNGPSKXYPRL-UHFFFAOYSA-N O=C(C1CCCCC1)N(CC(N1CCc2ccccc2)=O)CC1=O Chemical compound O=C(C1CCCCC1)N(CC(N1CCc2ccccc2)=O)CC1=O ASJGNGPSKXYPRL-UHFFFAOYSA-N 0.000 description 1
- URWGVJCAPYTBRW-UHFFFAOYSA-N OC(CN(C1)C(C2CCCCC2)=O)N(CCc2ccccc2)C1=O Chemical compound OC(CN(C1)C(C2CCCCC2)=O)N(CCc2ccccc2)C1=O URWGVJCAPYTBRW-UHFFFAOYSA-N 0.000 description 1
- 241001480233 Paragonimus Species 0.000 description 1
- 241000935974 Paralichthys dentatus Species 0.000 description 1
- 208000030852 Parasitic disease Diseases 0.000 description 1
- 241000242683 Schistosoma haematobium Species 0.000 description 1
- 241000242677 Schistosoma japonicum Species 0.000 description 1
- 241000242680 Schistosoma mansoni Species 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000002141 anti-parasite Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000013475 authorization Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- MPTQRFCYZCXJFQ-UHFFFAOYSA-L copper(II) chloride dihydrate Chemical compound O.O.[Cl-].[Cl-].[Cu+2] MPTQRFCYZCXJFQ-UHFFFAOYSA-L 0.000 description 1
- 230000006353 environmental stress Effects 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000000590 parasiticidal effect Effects 0.000 description 1
- 239000002297 parasiticide Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 201000004409 schistosomiasis Diseases 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
Abstract
The invention belongs to the field of medicine, and relates to a preparation method of a veterinary drug praziquantel, in particular to a novel method for preparing praziquantel. Raw materials such as chloracetyl chloride and glycin used in the method are low in cost and easy to obtain; the reaction is conventional; the operation is simple; the method has no special requirements on equipment; one step that a key intermediate 14 is subjected to intramolecular cyclization to form a compound 15 is designed in a reaction route; the design is brand-new and is not reported previously; the reaction yield is higher in the whole route; the total yield can reach 50%; most solvents used in a reaction process can be recovered, so that the cost is saved, and the environmental pressure is reduced; the cost is lowered extremely; and the route has a very good industrial application prospect.
Description
Technical field:
The present invention relates to the preparation method of a kind of veterinary drug praziquantel (Praziquantcl), belong to field of medicaments.
Background of invention:
Praziquantel has another name called Pyquiton, 8440, for the sick medication of broad-spectrum anti-parasite, Schistosoma japonicum, Schistosoma haematobium, Schistosoma mansoni etc. is all had killing action.In addition, it also has killing action to paragonimus (lung fluke), clonorchis sinensis, Echinococcus hydatid cyst, cysticercus, Meng Shi pleroceroid, fasciloopsis, tapeworm etc.Except being used for human body, praziquantel also is widely used as the parasiticide treatment of animal, poultry etc.
Praziquantel is at first synthetic in 1975 by people such as Seubere, and Merck KGaA and Bayer two pharmaceutical factory develops go out pharmaceutical preparation.Merck KGaA company in 1980 is with trade(brand)name " Cesol " listing that takes the lead in, and its effect characteristics are that curative effect is high, dosage is little, short treating period, metabolism is fast, toxicity is little and convenient oral, thereby welcome by the patient.Praziquantel is after listing, and sales volume constantly increases, and share of market enlarges rapidly, becomes very soon the choice drug for the treatment of in the world schistosomicide and multiple parasitosis.
In recent years, some national Schistosomiasis Epidemics enlarge to some extent in the world, and China's some areas schistosomicide also has the new line phenomenon.Therefore, strengthen the research of praziquantel new synthesis route is had important practical significance and practical value.
Praziquantel has the following formula chemical structure:
German patent DE 2504250 and DE2508947 have announced the early stage synthetic route of praziquantel:
This processing step is longer, and the reaction of 8 steps is arranged; Total recovery only is about 15%.To use severe poisonous chemicals prussiate toxicity in the production larger.Simultaneously, the high-pressure hydrogenation operating process in the production, dangerous large, easily have an accident.And three wastes discharge amount is large, and the environment protection treating expense is high.
For many years, people are studying the praziquantel new synthetic process always, have obtained in recent years many achievements.Especially 2005, the improvement that the people such as the Dan Yuhua of China Jiangsu Polytechnic University carry out Praziquantel synthetic process, applied for Chinese invention patent 200510037911.2, and obtained the authorization:
This technique obtains compound 9 take β-phenylethylamine, glycyl halogen hydrochlorate as raw material through condensation; Compound 9 is compound 10 with halo acetaldehyde acetal, is substituted reaction and obtains compound 11; Compound 11 cyclisation under strong acid condition obtains compound 7; Compound 7 is through the synthetic praziquantel of acidylate.
This synthetic reaction condition relaxes, atmospheric operation, and operational safety, synthesis step is succinct, and total recovery can surpass 50%; And the building-up process effluent discharge is few, pollutes littlely, is a kind of clean and effective synthesis technique.But some reagent of using in the process, for example glycyl halogen hydrochlorate, halo acetaldehyde acetal extremely are not easy to get, and price is higher, still has room for improvement.
Summary of the invention:
Main purpose of the present invention provides a kind of method for preparing praziquantel with low cost, simple to operation.
Technical scheme of the present invention is:
A kind of preparation method of praziquantel is characterized in that,
The first step β-phenylethylamine and chloroacetyl chloride reaction preparation compound 12,
Second step compound 12 prepares compound 13 with glycine reactant,
The 3rd step compound 13 and cyclohexanecarbonyl chloride reaction preparation compound 14,
The 4th step compound 14 carries out intramolecular cyclization and obtains compound 15,
The 5th step compound 15 obtains compound 16 through reducing,
The 6th step compound 16 carries out intramolecular cyclization under strong acid condition, obtain praziquantel, and namely compound 8,
The first step reaction is in the presence of sodium bicarbonate, slowly drip the mixing solutions of chloroacetyl chloride and this chloroparaffin in the chloroparaffin agent system that contains β-phenylethylamine, wherein the preferred methylene dichloride of chloroparaffin is controlled the interior temperature of reaction system and is no more than 10 ℃, preparation compound 12 in the dropping process;
The second step reaction is in the presence of organic bases, and compound 12 and glycine are at C
1-C
3In the alcohols, preparation compound 13 under the reflux conditions, the preferred triethylamine of organic bases wherein, C
1-C
3The alcohol particular methanol;
Three-step reaction is in the presence of alkali, and compound 13 and cyclohexanecarbonyl chloride are in chloroparaffin, and reaction prepares compound 14, the interior temperature of the hierarchy of control is no more than 10 ℃ in the process, the preferred methylene dichloride of chloroparaffin wherein, alkali is selected in sodium hydroxide, yellow soda ash, salt of wormwood, preferred salt of wormwood;
Four-step reaction be compound 14 under the effect of cyclization reagent, intramolecular cyclization occurs, obtain compound 15, wherein cyclization reagent is selected from acetic anhydride, sulfur oxychloride, preferred sulfur oxychloride; When cyclization reagent was acetic anhydride, acetic anhydride had both been done reaction solvent, did again the cyclization reagent of reaction; When cyclization reagent was sulfur oxychloride, reaction solvent was selected from chloroparaffin, preferred methylene dichloride;
The reaction of the 5th step is the reduction of compound 15, goes back original reagent and is selected from POTASSIUM BOROHYDRIDE, POTASSIUM BOROHYDRIDE/Copper dichloride dihydrate, preferred POTASSIUM BOROHYDRIDE/Copper dichloride dihydrate; Add in the reductive agent process, temperature is no more than 10 ℃ in the control in batches, and reaction solvent is selected from methyl alcohol, ethanol, Isosorbide-5-Nitrae-dioxane;
Six-step process is that compound 16 carries out cyclisation under the concentrated hydrochloric acid effect, obtains praziquantel.
The invention has the beneficial effects as follows the method for preparing praziquantel that a kind of novelty is provided.The method is raw materials used cheap and easy to get, for example chloroacetyl chloride, glycine; Reaction is conventional, and is simple to operate, and equipment is not had particular requirement; We have designed key intermediate 14 and carry out intramolecular cyclization and generate 15 1 steps of compound in the reaction scheme, and this is a brand-new design, has no bibliographical information; Whole piece route reaction yield is higher, and total recovery can reach 50%, and the solvent major part of using in the reaction process can reclaim, and has both saved cost, has alleviated again environmental stress, has greatly reduced cost, is a route that prospects for commercial application is arranged very much.
Embodiment:
Embodiment 1: the preparation of compound 12
122g phenylethylamine (1mol) and 92.4g sodium bicarbonate (1.1mol) be added in the 600mL methylene dichloride stir, ice bath is cooled to about 0 ℃, slowly drip the mixing solutions of 124.3g chloroacetyl chloride (1.1mol) and 120g methylene dichloride, after dropwising, be warming up to 25 ℃ and continue reaction 3h, 0-5 ℃ adds 200mL water in reaction solution, tell organic layer, with methylene dichloride (100mL*2) aqueous layer extracted, behind the combined dichloromethane layer, use anhydrous sodium sulfate drying, filter, remove methylene dichloride under reduced pressure, get the 189g white solid, yield 96%, fusing point: 120-125 ℃.
Embodiment 2: the preparation of compound 13
Get 19.7g (0.1mol) compound 12,12.1g triethylamine (0.12mol) is added in the 100mL methyl alcohol, stir 10min, temperature rising reflux stirs 8h after adding 9g (0.12mol) glycine, decompression steams methyl alcohol, in residue, add 50mL water and the stirring of 100mL methylene dichloride, standing demix is told dichloromethane layer, with methylene dichloride (50mL*2) washing water layer, the combined dichloromethane phase, anhydrous sodium sulfate drying, suction filtration steams methylene dichloride and gets brown solid, acetone recrystallization, get 20.1g off-white color solid, yield 85%, fusing point: 187-189 ℃.
Embodiment 3: the preparation of compound 14
1. with 23.6g compound 13 (0.1mol), 20.7g salt of wormwood (0.15mol) is added in 100g water and the 300mL methylene dichloride, be cooled to 0 ℃ under stirring, drip 17.5g (0.12mol) cyclohexanecarbonyl chloride, be warming up to stirring at room 3h after dropwising, tell dichloromethane layer, water layer extracts with methylene dichloride (100mL*2), the combined dichloromethane layer, anhydrous sodium sulfate drying, suction filtration, decompression steams methylene dichloride, add the 100mL sherwood oil in residue, stirring at room 1h, suction filtration get 30.5g off-white color solid, yield 88%, fusing point: 166-168 ℃.
2. with 23.6g compound 13 (0.1mol), 6g sodium hydroxide (0.15mol) is added in 250mL methylene dichloride and the 100mL water mixed liquid, be cooled to 0 ℃ under stirring, drip 17.5g (0.12mol) cyclohexanecarbonyl chloride, be warming up to backflow after dropwising, stir 5h, be cooled to room temperature, add 100mL water in reaction solution, tell dichloromethane layer, water layer extracts with methylene dichloride (50mL*2), the combined dichloromethane layer, anhydrous sodium sulfate drying, suction filtration, decompression steams methylene dichloride, in residue, add the 100mL sherwood oil, stirring at room 1h, suction filtration gets 21.2g off-white color solid, yield 85%, fusing point: 166-168 ℃.
Embodiment 4: the preparation of compound 15
1. 34.6g (0.1mol) compound 14 is added in the 150mL toluene, is cooled to about 0 ℃ under stirring, drip 13.1g sulfur oxychloride (0.11mol), dropwise under the rear room temperature and stir 1h, be warming up to 50 ℃ and stir 2h, temperature rising reflux stirs 4h, step-down solvent evaporated, in residue, add 200mL water under the room temperature, abundant stirring to pulp 2h, suction filtration, the dehydrated alcohol recrystallization gets the 27.9g white solid, yield 85%, fusing point: 91-93 ℃.
2. 34.6g (0.1mol) compound 14 is added in the 200mL acetic anhydride, stirs and be warming up to backflow, behind the insulated and stirred 3h, be chilled to room temperature, after stirring 2h, suction filtration, 50mL water washing filter cake, the dehydrated alcohol recrystallization gets the 24.6g white solid, yield 75%, fusing point: 91-93 ℃.
Embodiment 5: the preparation of compound 16
1. 16.4g (0.05mol) compound 15 is added in the 50mL methyl alcohol, stirring is cooled to 0 ℃, in reaction solution, add the 8.4g Copper dichloride dihydrate, continue insulated and stirred 0.5h, add the 13.5g POTASSIUM BOROHYDRIDE in batches, insulated and stirred 1h, the step-down solvent evaporated adds 20mL water in residue, 0 ℃ drips 1N hydrochloric acid, transfer about pH to 6, ethyl acetate (50mL*2) extraction, 10% sodium bicarbonate aqueous solution washs once, and salt solution tries once, anhydrous sodium sulfate drying, decompression steams solvent, and gained material isopropyl ether recrystallization obtains the 14.2g white solid, yield 86%, fusing point: 136.5-138.5 ℃.
2. 16.4g (0.05mol) compound 15 is added in 80mL dioxane and the 5mL water, stirs and be cooled to 15 ℃, in reaction solution, add the 15g POTASSIUM BOROHYDRIDE in batches, stirring at room 1h, be warming up to 60 ℃, stir 2h, be down to room temperature, suction filtration, the filter cake washing, gained material isopropyl ether recrystallization gets the 10.9g white solid, yield 80%, fusing point: 136.5-138.5 ℃.
Embodiment 6: the preparation of praziquantel
100mL concentrated hydrochloric acid (12N) is added in the reaction flask, be cooled to 0 ℃, stir the lower 9.9g compound 16 (0.03mol) that in batches adds, 0 ℃ is stirred 1h, be warming up to stirring at room 20h, in reaction solution, add 200mL cold water, methylene dichloride (100mL*3) extraction, anhydrous sodium sulfate drying, step-down is steamed and is desolventized, re-crystallizing in ethyl acetate obtains 8.7g white solid praziquantel, yield 93%, fusing point: 133-136 ℃.
Claims (7)
1. the preparation method of a praziquantel is characterized in that,
The first step β-phenylethylamine and chloroacetyl chloride reaction preparation compound 12,
Reaction solvent is selected from chloroparaffin;
Second step compound 12 prepares compound 13 with glycine reactant,
Reaction solvent is selected from C
1-C
3Alcohols;
The 3rd step compound 13 and cyclohexanecarbonyl chloride reaction preparation compound 14,
Reaction solvent is selected from chloroparaffin;
The 4th step compound 14 carries out intramolecular cyclization and obtains compound 15,
React solvent-free or solvent and be selected from a kind of in toluene, the chloroparaffin;
The 5th step compound 15 obtains compound 16 through reducing,
Reaction solvent is selected from a kind of in methyl alcohol, ethanol or the Isosorbide-5-Nitrae-dioxane;
The 6th step compound 16 carries out intramolecular cyclization under strong acid condition, obtain praziquantel, and namely compound 8,
2. preparation method according to claim 1 is characterized in that the used alkali of three-step reaction is selected from a kind of in sodium hydroxide, yellow soda ash or the salt of wormwood.
3. preparation method according to claim 1 is characterized in that the used cyclization reagent of four-step reaction is selected from acetic anhydride or sulfur oxychloride.
4. preparation method according to claim 1 is characterized in that the used reductive agent of the 5th step reaction is POTASSIUM BOROHYDRIDE or POTASSIUM BOROHYDRIDE/Copper dichloride dihydrate.
5. preparation method according to claim 1 is characterized in that the first step reaction solvent for use is selected from methylene dichloride.
6. preparation method according to claim 1 is characterized in that second step reaction solvent for use is selected from methyl alcohol.
7. preparation method according to claim 1 is characterized in that the three-step reaction solvent for use is selected from methylene dichloride.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210595943.4A CN103044422B (en) | 2012-12-27 | 2012-12-27 | A kind of preparation method of praziquantel |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210595943.4A CN103044422B (en) | 2012-12-27 | 2012-12-27 | A kind of preparation method of praziquantel |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103044422A true CN103044422A (en) | 2013-04-17 |
| CN103044422B CN103044422B (en) | 2016-06-08 |
Family
ID=48057306
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210595943.4A Active CN103044422B (en) | 2012-12-27 | 2012-12-27 | A kind of preparation method of praziquantel |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103044422B (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105622606A (en) * | 2016-04-06 | 2016-06-01 | 宜兴市新宇化工有限公司 | Preparation method of praziquantel |
| WO2016127350A1 (en) * | 2015-02-12 | 2016-08-18 | 浙江海正药业股份有限公司 | Preparation method for praziquantel and intermediate compounds thereof |
| CN108794466A (en) * | 2017-04-26 | 2018-11-13 | 苏州同力生物医药有限公司 | A kind of amorphous levo-praziquantel solid and its preparation method and application |
| CN111995539A (en) * | 2020-09-28 | 2020-11-27 | 郑州原理生物科技有限公司 | Preparation method of lidocaine hydrochloride impurity E |
| CN115677528A (en) * | 2022-11-03 | 2023-02-03 | 厦门稀土材料研究所 | Method for separating rhenium and technetium |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4497952A (en) * | 1982-07-08 | 1985-02-05 | Korea Advanced Institute Of Science And Technology | Process for the production of (±)-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline derivatives |
| CN1683346A (en) * | 2005-03-01 | 2005-10-19 | 江苏工业学院 | Praziquantel synthetic process |
| WO2009115333A1 (en) * | 2008-03-20 | 2009-09-24 | Doemling Alexander | Novel synthesis of praziquantel |
-
2012
- 2012-12-27 CN CN201210595943.4A patent/CN103044422B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4497952A (en) * | 1982-07-08 | 1985-02-05 | Korea Advanced Institute Of Science And Technology | Process for the production of (±)-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline derivatives |
| CN1683346A (en) * | 2005-03-01 | 2005-10-19 | 江苏工业学院 | Praziquantel synthetic process |
| WO2009115333A1 (en) * | 2008-03-20 | 2009-09-24 | Doemling Alexander | Novel synthesis of praziquantel |
Non-Patent Citations (1)
| Title |
|---|
| DANIEL FREHEL ET AL.: ""New syntheses of praziquantel:2-(cyclohexylcarbonyl)-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin-4-one"", 《HETEROCYCLES》, vol. 20, no. 9, 31 December 1983 (1983-12-31), pages 1731 - 1735, XP009120024, DOI: doi:10.3987/R-1983-09-1731 * |
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2671202C1 (en) * | 2015-02-12 | 2018-10-30 | Чжэцзян Хисун Фармасьютикал Ко., Лтд. | Method for obtaining praziquantel and its intermediate compounds |
| KR101960347B1 (en) | 2015-02-12 | 2019-03-20 | 쯔지앙 하이썬 파머슈티컬 컴퍼니, 리미티드 | Method for preparing praziquantel and its intermediate compounds |
| KR20170117165A (en) * | 2015-02-12 | 2017-10-20 | 쯔지앙 하이썬 파머슈티컬 컴퍼니, 리미티드 | Method for preparing praziquantel and its intermediate compounds |
| CN107406444A (en) * | 2015-02-12 | 2017-11-28 | 浙江海正药业股份有限公司 | A kind of Preparation Method And Their Intermediate compound of praziquantel |
| JP2018506586A (en) * | 2015-02-12 | 2018-03-08 | 浙江▲海▼正▲薬▼▲業▼股▲フン▼有限公司 | Method for producing praziquantel and its intermediate compound |
| US10035798B2 (en) | 2015-02-12 | 2018-07-31 | Zhejiang Hisun Pharmaceutical Co., Ltd. | Preparation method for praziquantel and intermediate compounds thereof |
| WO2016127350A1 (en) * | 2015-02-12 | 2016-08-18 | 浙江海正药业股份有限公司 | Preparation method for praziquantel and intermediate compounds thereof |
| CN107406444B (en) * | 2015-02-12 | 2019-07-23 | 浙江海正药业股份有限公司 | A kind of Preparation Method And Their Intermediate compound of praziquantel |
| US10508112B2 (en) | 2015-02-12 | 2019-12-17 | Zhejiang Hisun Pharmaceutical Co., Ltd. | Intermediate compounds for preparation of praziquantel and processes for preparing the intermediate compounds |
| CN105622606A (en) * | 2016-04-06 | 2016-06-01 | 宜兴市新宇化工有限公司 | Preparation method of praziquantel |
| CN108794466A (en) * | 2017-04-26 | 2018-11-13 | 苏州同力生物医药有限公司 | A kind of amorphous levo-praziquantel solid and its preparation method and application |
| CN111995539A (en) * | 2020-09-28 | 2020-11-27 | 郑州原理生物科技有限公司 | Preparation method of lidocaine hydrochloride impurity E |
| CN111995539B (en) * | 2020-09-28 | 2023-08-11 | 郑州原理生物科技有限公司 | Preparation method of lidocaine hydrochloride impurity E |
| CN115677528A (en) * | 2022-11-03 | 2023-02-03 | 厦门稀土材料研究所 | Method for separating rhenium and technetium |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103044422B (en) | 2016-06-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103044422A (en) | Preparation method of praziquantel | |
| CN103961340B (en) | A kind of LSD1 inhibitor and its application | |
| CN101891728B (en) | Scutellarein derivative as well as preparation method and application thereof | |
| CN101362702B (en) | Emodin derivates and application thereof in anti-cancer medicine preparation | |
| KR20130143084A (en) | Process and intermediates for preparing macrolactams | |
| CN102060769B (en) | Preparation method of tolvaptan | |
| CN101824017B (en) | Method for preparing scutellarin aglycone | |
| CN101735190B (en) | Method for preparing baicalein | |
| CN107573333B (en) | The preparation method of intermediate of ticagrelor and preparation method thereof and ticagrelor | |
| CN109988167A (en) | A kind of preparation method of Tadalafei | |
| CN104910119A (en) | Coumarin substituted flavonoid derivatives, and preparation method and application thereof | |
| CN105175317B (en) | A kind of method for preparing picosulfate sodium | |
| CN105175316B (en) | A kind of method for preparing laxative picosulfate sodium | |
| CN103059018A (en) | Praziquantel preparation process | |
| CN107043385A (en) | A kind of method for preparing DRV intermediate | |
| CN103319455B (en) | Preparation method of high-purity strontium ranelate | |
| CN103172638B (en) | A kind of preparation method of Epinastine Hydrochloride | |
| CN102731459A (en) | Scutellarin aglycone Mannich derivatives, and preparation method and application thereof | |
| CN101891689B (en) | Preparation method of hydrochloric acid gamma-hydroxy bendamustine | |
| CN106349141A (en) | Polyhydroxylated pyrrolidine compound as well as preparation method and application thereof | |
| CN102180878B (en) | Dolasetron isomer or salt thereof, preparation method for the Dolasetron isomer or salt thereof and application of the Dolasetron isomer or salt thereof | |
| CN110183446A (en) | A kind of new impurity of Moxifloxacin and its preparation method and use | |
| CN105061430A (en) | Preparation method of anti-tumor compound and application of compound | |
| CN104326960A (en) | Method for preparing Boc-L-proline | |
| CN109293587A (en) | The preparation method of Clofazimine and its intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| ASS | Succession or assignment of patent right |
Owner name: DISHA PHARMACEUTICAL INDUSTRY GROUP CORP., LTD. Free format text: FORMER OWNER: WEIHAI DIZHIYA PHARMACHEM. DEVELOPMENT CO., LTD. Effective date: 20150908 Free format text: FORMER OWNER: DISHA PHARMACEUTICAL INDUSTRY GROUP CORP., LTD. DISHA PHARMACEUTICAL GROUP SHANDONG DISHA PHARMACEUTICAL CO., LTD. Effective date: 20150908 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20150908 Address after: 264205 No. 1 South Qingdao Road, Weihai economic and Technological Development Zone, Shandong, China Applicant after: DISHA PHARMACEUTICAL GROUP Co.,Ltd. Address before: 264205 Shandong city of Weihai province by the district Gushan Town No. 18 South Road, No. 19 North Road, No. 3 East Road, the west five Applicant before: WEIHAI DIZHIYA PHARMACHEM DEV Co.,Ltd. Applicant before: DISHA PHARMACEUTICAL GROUP Co.,Ltd. Applicant before: Shandong Disha Pharmaceutical Co.,Ltd., Disha Phamaceutical Group |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20210430 Address after: 264205 Wendeng economic and Technological Development Zone, Weihai City, Shandong Province Patentee after: Dijia Pharmaceutical Group Co.,Ltd. Address before: No.1 Qingdao South Road, Weihai Economic and Technological Development Zone, Shandong Province Patentee before: DISHA PHARMACEUTICAL GROUP Co.,Ltd. |
|
| CP02 | Change in the address of a patent holder | ||
| CP02 | Change in the address of a patent holder |
Address after: 264205 268 Tianrun Road, Wendeng economic and Technological Development Zone, Weihai, Shandong Patentee after: Dijia Pharmaceutical Group Co.,Ltd. Address before: 264205 Wendeng economic and Technological Development Zone, Weihai City, Shandong Province Patentee before: Dijia Pharmaceutical Group Co.,Ltd. |
|
| CP03 | Change of name, title or address | ||
| CP03 | Change of name, title or address |
Address after: No. 268, Tianrun Road, Wendeng Economic and Technological Development Zone, Weihai City, Shandong Province, 264200 Patentee after: Dijia Pharmaceutical Group Co.,Ltd. Address before: 264205 268 Tianrun Road, Wendeng economic and Technological Development Zone, Weihai, Shandong Patentee before: Dijia Pharmaceutical Group Co.,Ltd. |